Treponema pallidum pallidum

Background

• Causes syphilis

Microbiology

• Small, slow-growing spirochete
• Not seen on standard microscopy; requires darkfield microscopy

Clinical Manifestations

Overview of Stages

• Primary syphilis (incubation period 3 weeks [range 3 to 90 days])
• Secondary syphilis (incubation period 2 weeks to 3 months [range 2 weeks to 6 months])
• Latent
  • Early latent (<1 year)
  • Late latent (≥1 year)
• Tertiary syphilis (incubation period years to decades)
  • Cardiovascular (incubation period 10 to 30 years)
  • Gummatous (incubation period 15 years [range 1 to 46 years])
  • Neurosyphilis (incubation period 2 to 20 years)
    • Meningovascular
    • Parenchymatous
    • Tabes dorsalis
• Congenital
  • Early (< 2 years)
  • Late (≥ 2 years)

Primary Syphilis

• Incubation period is about 3 weeks
• Chancre
• Genital ulcer disease
  • Clean borders
  • Indurated
  • Not painful unless secondarily infected
  • Lasts 2 to 6 weeks
• May present with regional lymphadenopathy
• Diagnosis with darkfield microscopy, fluorescent antibody smear, or (most commonly) serology
• Serology often negative in early syphilis

Secondary Syphilis

• Incubation period 3 weeks to 3 months
• Often no history of chancre
• Diffuse maculopapular rash that involves palms and soles
  • Typically begins on trunk
  • Start as pinkish-reddish macular lesions that evolve into brownish-reddish papules that may have scaling
  • May progress to pustular lesions (pustular syphilids)
  • May be itchy
  • Can be isolated to palms and soles
• Generalized lymphadenopathy
• Fever, chills, arthralgias
• Less common: condyloma lata, aseptic meningitis, iritis, mucosal white patches, glomerulonephritis, paroxysmal nocturnal hemoglobinuria, hepatitis
• This is the most common time to develop ocular involvement, including:
  • Anterior uveitis (usually unilateral though can become bilateral)
  • Posterior involvement with vitritis, necrotizing retinitis, chorioretinitis, retinal vasculitis, and optic neuritis (usually toward the end of secondary syphilis)
    • Chorioretinitis is the most common
  • Acute posterior placoid chorioretinopathy (in secondary or late latent syphilis)

Latent Syphilis

• Defined as asymptomatic and untreated but with positive serology
  • Can be early latent (<1 year) or late latent (≥1 year)
  • If unknown duration, late latent is assumed
• High rate of relapse of secondary syphilis within the first 1-2 years following infection (but especially within the first year)

Tertiary Syphilis

• Eventually occurs in about 30% of untreated cases

Neurosyphilis

• Of the 25-60% of people who have CNS invasion, 95% are asymptomatic during the early stage and 80% of those spontaneously clear it
• Incubation period is 7-15 years
• Three major presentations: meningovascular syphilis, parenchymous syphilis, and tabes dorsalis

Meningovascular

• Possibly the most common neurosyphilis
• Subdivided into cerebromeningeal (diffuse or focal) and cerebrovascular
• Stroke-like symptoms, especially MCA or basilar territory
• Can present as a sudden change, as syphilitic apoplexy
• Can present following a prodrome of weeks to months of non-specific headaches, vertigo, irritability, insomnia, and personality changes

Parenchymatous

• Previously known as "generalized paresis of the insane"
• Occurs in 2-5% of cases of untreated syphilis
• Commonly found on psychiatric wards
• Causes psychosis and dementia
• Later, coarse tremors, Argyll-Robinson pupil, paresis

Tabes Dorsalis

• Occurs in 2-9% of cases of untreated syphilis
• Isolated posterior cord degeneration leading to a loss of proprioception in the lower extremities
• Stomp the ground when walking to use intact pain/pressure sensation
• Loss of sensation in the Hitzig zones (tip of nose, band including nipple area, medial forearms, and lateral leg)
• Can present with Charcot foot and, rarely, recurrent abdominal pain
• Diagnosed by serum CMIA, but RPR may be negative

Others

• Isolated ocular neurosyphilis
• Meningitis: can present at any time during the course of disease
• Others

Cardiovascular Syphilis

• Occurs in 10% of people with untreated syphilis
• Incubation period is 20-25 years
• Aortic root involvement leading to aortitis and dilatation
• May result in aneurysm, aortic insufficiency, or angina secondary to stenosis at the aortic root
• Diagnosed by RPR +/- CMIA

Gummatous Syphilis

• Gummas are necrotizing granulomatous lesions
• Occurs in 15% of people with untreated syphilis
• Incubation period 6-8 years
• Gummas may appear anywhere, in any organ, but most commonly on the skin, on mucosa, and in bones
• CNS lesions look like toxo, so beware in HIV patients

Other Presentations

• Isolated auditory syphilis
• Isolated optic syphilis
• Syphilitic osteitis and osteomyelitis, which can present in any stage

Congenital Syphilis

• May be either early (<2 years old) or late (≥2 years old)
• Classic Hutchison triad is interstitial keratitis, cranial nerve VIII deafness, and abnormal teeth
• See Congenital syphilis for more information

Diagnosis

• Often done as non-treponemal test to screen, followed by treponemal test to confirm
• In Ontario, we do a treponemal test to screen (CMIA), then repeat it with a more specific treponemal test (TPPA) alongside RPR

Direct Visualization

• Darkfield microscopy
  • Chancre cleaned and smear obtained
  • Smear must be visualized immediately
  • Sensitivity decreases with duration
• Smear for fluorescent monoclonal antibody
  • Best to use in primary syphilis, with a swab from the base of the lesion
  • Can be done by Public Health Ontario

Non-Treponemal Tests (VDRL/RPR)

• Veneral Diseases Research Laboratory (VDRL) has been replaced by the rapid plasma reagin (RPR) test
  • Quantitative tests for a non-specific anti-cardiolipin antibody that is produced in syphilitic (and other) infections
• False positives:
  • Acute biologic false positive: malaria, brucellosis, and mononucleosis; maybe pregnancy
  • Chronic biologic false positive: lupus and other autoimmune disorders, HIV, intravenous drug use, and leprosy
• Only 50% sensitive in primary, 100% sensitive in secondary
• Tests wane over time, and can eventually become nonreactive in late latent or tertiary syphilis

Treponemal Tests

• More specific and sensitive, but more expensive
• False positives: lupus and other autoimmune disorders, Lyme disease, and other treponemal infections
• Remain positive for life
• Four main tests:
  • Fluorescent treponemal antibody absorption (FTA-Abs): Essentially the gold standard
  • Chemoluminescnence microparticle immunoassay (CMIA or CLIA): the screening test used in Ontario. Often used as a screening test as it is an easily-automated immunoassay and is more sensitive and specific than RPR.
  • Treponema pallidum Particulate Agglutination assay (TPPA): a modification of the TPHA. Used as the confirmatory test (alongside RPR) used in Ontario.
  • T. pallidum hemagglutination assay (TPHA): very old test.
  • T. pallidum enzyme immunassay (TP-EIA)

Interpretation of Serology

CMIA screen	RPR	TPPA	Interpretation
Non-reactive	—	—	Negative result; or early syphilis (consider repeat in 4 weeks)
Reactive	Reactive	Reactive	Recent or prior syphilis infection
Reactive	Non-reactive	Reactive	Early primary syphilis, prior infection, late latent infection, prozone effect
Reactive	Non-reactive	Non-reactive	False positive; or early primary syphilis, previously treated, or late latent (repeat in 4 weeks)
Reactive	Non-reactive	Indeterminate	Inconclusive result; false positive, early syphilis, old treated syphilis, or old untreated syphilis (repeat in 4 weeks)
Reactive	Reactive	Non-reactive	Inconclusive result; false positive, early syphilis, old treated syphilis, or untreated syphilis (repeat in 4 weeks)
Reactive	Reactive	Indeterminate	Recent or prior syphilis infection

Lumbar Puncture for CSF

• Should be done routinely when:
  • Neurological (including optic and auditory) signs or symptoms
  • Failure of serologic response
  • Tertiary syphilis
  • Congenital syphilis
  • In patients with HIV: CD4 ≤350 and RPR ≥1:32
• The sample should be sent for cell count and differential, protein, and either VDRL (not RPR) or FTA-Abs
  • RPR is specific but less sensitive; it helps to rule in CNS disease when present
  • FTA-Abs is sensitive but less specific; it help to rule out CNS disease when absent

Management

• The standard first-line therapy is penicillin
  • It is the only antibiotic with proven efficacy in neurosyphilis and pregnancy
• In cases of allergy, desensitization is generally preferred to the second-line therapy of doxycycline
• A distant third-line option is ceftriaxone, only used when the others absolutely cannot given the lack of clinical data
• Azithromycin should not be used, given high rates of resistance
• Treatment may be complicated by a Jarisch-Herxheimer reaction
• Patients should avoid unprotected sexual contact until 1 week after completing treatment

Syndrome	First-Line	Alternative
Primary syphilis	benzathine penicillin G 2.4 MU IM once	doxycycline 100 mg PO bid for 14 days ceftriaxone 1 g IV/IM daily for 10 days
Secondary syphilis
Early latent syphilis
Late latent syphilis	benzathine penicillin G 2.4 MU IM weekly x3	doxycycline 100 mg PO bid for 30 days ceftriaxone 1 g IV/IM daily for 10 days
Tertiary syphilis
Neurosyphilis	penicillin G 4 MU IV q4h for 10-14 days	desensitization ceftriaxone 2 g IV/IM q24h for 10-14 days

Primary, Secondary, and Early Latent

• Benzathine penicillin G 2.4 million units IM once, divided between two buttocks
• Alternative (penicillin allergy): doxycycline 100mg BID for 2 weeks
• Alternative (penicillin allergy and pregnancy): penicillin desensitization or azithromycin
• Monitor serologic response with RPR titres at 3, 6, and 12 months, and until negative or stable low titre
  • Primary should decrease 4-fold at 6 months and 8-fold at 12 months
  • Secondary should decrease 8-fold at 6 months and 16-fold at 12 months
  • Early latent should decrease 4-fold at 12 months

Late Latent and Tertiary (excluding neurosyphilis)

• Benzathine penicillin G 2.4 million units IM q1week for 3 weeks
• Alternative (penicillin allergy): doxycycline for 30 days
• Monitor serologic response with RPR titres at 12 and 24 months, and until negative or stable low titre

Tertiary Neurosyphilis

• Penicillin G 4 million units IV q4h for 10 to 14 days
• Often followed by at least one dose of IM benzathine penicillin, sometimes weekly for 2-3 weeks
• For early neurosyphilis, the alternative of doxycycline 100 mg p.o. BID for 28 days may be noninferior1
• Monitor serologic response with RPR titres at 6, 12, and 24 months, and until negative or stable low titre
• Repeat lumbar puncture every 6 months until parameters normalize
  • Pleocytosis normalizes first, within 6 months, followed by protein levels over months to years
  • CSF-VDRL should decrease 4-fold in 12 month if it is high, but can persist for years until negative

Pregnancy

• Only penicillin is recommended, including desensitization if needed for allergy
• Some expoerts recommend a second dose of benzathine penicillin G 2.4 MU IM a week after the first dose for primary, secondary, or early latent syphilis

HIV Coinfection

• Treat as above
• Regardless of stage, monitor response with RPR titres at 3, 6, 12, and 24 months, then annually
• CSF parameters normalize more slowly in people with HIV

Congenital Syphilis

• If <1 month of age: crystalline penicillin G 50 kU/kg IV q12h for the first week of life and q8h thereafter, for a total of 10 days
• If ≥1 month of age: crystalline penicillin G 50,000 units/kg IV every 6 hours for 10-14 days
  • If there is no neurological involvement, then you can consider benzathine penicillin G 50 kU/kg (max 2.4 MU) IM weekly for 3 weeks

Follow-Up RPR

• RPR should be trended after treatment to ensure response, and repeated until negative (or stably low titre)
• It should be remeasured on the day of treatment, as it will often change significantly from diagnosis, even if it has only been a few days

Prevention

Public Health

• Contact tracing should be performed, identifying contacts within the presumed maximum incubation/latency period
  • Primary syphilis: 3 months
  • Secondary syphilis: 6 months
  • Early latent syphilis: 1 year
  • Late latent or tertiary syphilis: as appropriate
• Contacts should be tested, and treated if positive
• Reasonable to empirically/epidemiologically treat contacts from the previous 90 days if loss-to-follow-up is likely

Further Reading

• Toronto Public Health Syphilis Laboratory Interpretation and Treatment (2-page PDF)
• Canadian Guidelines on Sexually Transmitted Infections: Syphilis